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Introducing Milligram Screening Reactions into the Kilogram World of Chemical Development Simon Yates, AstraZeneca. FreeSlate European User Meeting 24 th September 2013

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Our Journey so far…

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We produce a scalable process, not just a compound From a few grams in the lab to multi-kilo plant campaigns Emphasis on SELECT criteria Safety Economics Legal Environment Control Throughput What is Chemical Development?

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In number of metal catalysed reactions in Med Chem The time to develop process for early compounds Development time by using scavengers Of scavengers and carbons to choose from Time, effort and missed opportunity by automated screening Reproducibility by screening under inert conditions Scavenging Challenge? Transition Metals are toxic! Conventional work up takes time to develop

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What are scavengers?

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But what kit? 10 reactions at a time Minimum volume ~2mL Integrity 10

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In number of reactions we could run (up from 24) Manual intervention, to make this as routine as possible Ease of programming and data analysis ‘ Future proof’ our investment Reaction scale Wanted to….

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We have run 20+ screens and saved projects time and money Numerous examples of where scavengers used in all scales of manufacture Pd is most common metal scavenged, now have a generic plate of 22 scavengers. Improvements in whole workflow reduced time from 5 working days to 2 days. Scavenging today

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Cross Coupling R 1 -M R 2 -X R 1 -R 2

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Background Original plan was to run X-Coupling Timing forced by closure of our existing facility In number of reactions we could run cover more experimental space, quicker. Reaction scale Apply our previous learning

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Future improvements Sampling always run at the end, not good for fast reactions Allow sampling as part of ‘dispense’ And/or move vials to heat zones to ‘start’ reactions (Josh Denette and Kristin Price at Pfizer)

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Data Handling RAS MDB

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Asymmetric Hydrogenation Successfully built capability in Sodertalje, Sweden site end of 2012 Opportunity to purchase new equipment CM3 (in glovebox) and SPR Off deck hydrogenation – make use of CM3 during long reactions Knowledge of LEA / CM2 CM2 / CM3 used as 1 resource for X-Coupling and Asymm. Hydrog. Commissioning - NOW

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Conclusion We have come along way since 2007 Scavenger was the warm up act Scavenging and X-Coupling saved millions of dollars already Success led the way to keep Asymm. Hydrog. in house Asymm. Hydrog. will have similar if not bigger impact Continue to develop workflows Keep control of the data 96 x 2 x 5 x 50 = 48K data points / year

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Conclusion User community carry on sharing and learning What’s good for me, could be good for you too.

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Acknowledgments

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Freeslate, San Francisco, 2013

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Confidentiality Notice This file is private and may contain confidential and proprietary information. If you have received this file in error, please notify us and remove it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful. AstraZeneca PLC, 2 Kingdom Street, London, W2 6BD, UK, T: +44(0) , F: +44 (0) ,

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What it looks like under the hood

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Time Out.… Accurate Sampling Accuracy and Precision of sampling critical for ICP analysis Narrower needle Use as small an airgap (20uL) No bubbles in your backing solvent Use a suitably large overshoot If sampling hot, aspirate an airgap before coming out of the vessel Dispense below solvent level if possible. Best syringe speeds (parameters) – varies for different solvents. Use DoE to define

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Start Speed Top Speed Cut Off SpeedSlope Option Time Speed What are these syringe parameters? Speeds for 500uL syringe

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A B C D Tare all 48 vials For each well Aspirate 100uL Toluene, plus 30uL overshoot from a 20mL vial Dispense into the 1mL vial using given parameters Immediately reweigh vial Calculate the volume dispensed by change in mass Randomised Speed Options, in triplicate Gravimetric checking

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For 100uL of toluene, at 25C Start SpeedTop SpeedCut Off SpeedSlope Option The result…

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For 100uL of toluene, at 25C Start SpeedTop SpeedCut Off SpeedSlope Option The result… 12 different solvents A range of speed options shown to be best 2-MeTHF – option 3 THF – option 16